The long-term goal of the proposed research is the development of more efficacious technetium-diphosphonate radiopharmaceuticals for use as skeletal (and other calcium site) imaging agents in diagnostic nuclear medicine. Within this overall goal, we seek to isolate and develop distinct calcium site imaging agents, each of which has properties optimized to provide diagnostic information on a given pathological condition. These objectives will be accomplished by the development of analytical techniques which are capable of separating clinically used radiopharmaceutical mixtures into their component technetium-diphosphonate complexes. High performance liquid chromatography with electrochemical detection will be developed as the primary analytical technique. Thin-layer spectroelectrochemistry will be used to define oxidation states of the separated technetium-diphosphonate complexes. Research will be initiated with technetium-hydroxyethylidine diphosphonate, a clinically used radiopharmaceutical, and extended to complexes of other bone-seeking ligands such as methylene diphosphonate and hydroxymethylene diphosphonate. The relative imaging efficacy of the individual complexes will be evaluated in animal models. Correlations between imaging efficacy and the oxidation state and/or composition of the various technetium-diphosphonate complexes will be evaluated to determine if individual components have different in vivo distributions. Of particular long-range significance will be the identification of the component(s) that has the highest lesion/normal tissue distribution, since the use of this isolated component will enhance our ability to detect bone cancer early in the course of the disease. Administration of the isolated, single most effective imaging complex, rather than a mixture of technetium-containing complexes (as is the current clinical practice), will minimize radiation exposure to the patient and maximize diagnostic information available to the clinician.